Disease relevance of L-Oddc

• A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy [1].
• PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia [2].
• Troxacitabine merits further study in hematologic malignancies [2].
• Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this [3].
• DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination [4].

High impact information on L-Oddc

• PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma [3].
• Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia [1].
• DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination [4].
• CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash [3].
• Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cl(s)) were 60 (32) L and 161 (33) mL/min, respectively, on day 1 [5].

Chemical compound and disease context of L-Oddc

• PURPOSE: Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin [1].
• Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias [4].
• A troxacitabine-resistant prostate cancer subline (DU145(R); 6300-fold) that exhibited reduced uptake of troxacitabine was cross-resistant to both gemcitabine (350-fold) and cytarabine (300-fold). dCK activity toward deoxycytidine in DU145(R) cell lysates was <20% of that in DU145 cell lysates, and no activity was detected toward troxacitabine [6].
• PURPOSE: Troxacitabine (beta-L-dioxolane cytidine, BCH-4556; Troxatyl, BioChem Pharma Inc.) is a novel nucleoside analogue, which in experiments demonstrated potent antitumor activity against both leukemias and solid tumors [7].
• Since troxacitabine is a cytidine nucleoside analogue like AraC (1-beta-D-arabinofuranosylcytosine), which is currently used in the treatment of acute myelogenous leukemia, we compared the in vivo antileukemic activity of troxacitabine with that of AraC in human leukemia xenograft models [7].

Biological context of L-Oddc

• PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m(2), based on toxicology data from the most sensitive species studied (cynomolgus monkey) [8].
• Sequence analysis of cDNAs encoding dCK revealed a mutation of a highly conserved amino acid (Trp(92)-->Leu) in DU145(R) dCK, providing a possible explanation for the reduced phosphorylation of troxacitabine in DU145(R) lysates [6].
• RESULTS: Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines [9].
• In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0.01 micromol/l) with either IM-sensitive or resistant disease [10].
• Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP [11].

Anatomical context of L-Oddc

• The current work was undertaken to identify potential biochemical mechanisms of resistance to troxacitabine and to determine whether there are differences in resistance mechanisms between troxacitabine, gemcitabine, and cytarabine in human leukemic and solid tumor cell lines [6].
• Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines [12].
• In a cohort of 170 patients with refractory myeloid leukemia treated with troxacitabine-based regimens on Phase 1 or 2 studies, 10 (6%) had biopsy-proven extramedullary disease, either with or without bone marrow involvement [13].

Associations of L-Oddc with other chemical compounds

• Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytidine), a deoxycytidine analogue with an unusual dioxolane structure and nonnatural L-configuration, has potent antitumor activity in animal models and is in clinical trials against human malignancies [6].
• Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue [14].
• Several agents are being investigated for treatment of advanced-phase CML, including decitabine (DAC), homoharringtonine (HHT), troxacitabine, clofarabine, farnesyl transferase (FTase) inhibitors (FTI), and others [15].
• The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK [11].

Gene context of L-Oddc

• This unusual property led us to evaluate the efficacy of troxacitabine in multidrug resistant (MDR) and multidrug resistance-associated protein (MRP) tumors [16].
• RESULTS: Troxacitabine demonstrated potent antiproliferative activity against both P-glycoprotein-positive (KBV, HL60/R10, CCRF-CEM/VLB) and P-glycoprotein-negative (HL60/ADR) multidrug-resistant cell lines with IC(50) values ranging from 7 to 171 n M [16].
• The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2) [2].
• CONCLUSIONS: Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability [14].
• Troxacitabine, which in contrast to AraC is not a substrate for cytidine deaminase, showed potent in vitro and in vivo activity in the same model (IC50 = 53 nM and T/C = 272% to 422%) [7].

Analytical, diagnostic and therapeutic context of L-Oddc

• PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks [3].
• The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model [9].
• The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls [17].
• The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size [14].
• Here, we report six cases of troxacitabine-induced PPES that was later recalled by various chemotherapy regimens [18].

References